Process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives

ABSTRACT

Invented is an improved process for preparing aromatic ring-fused cyclopentane derivatives. Preferred compounds prepared by this invention are indane carboxylates and cyclopentano[b]pyridine derivatives. The most preferred compounds prepared by this inventino are (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+)(1S,2R,3S)-3-[(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof. Also invented are novel intermediates useful in preparing these compounds.

FIELD OF THE INVENTION

[0001] The present invention relates to an improved process forpreparing aromatic ring-fused cyclopentane derivatives. Preferably, thepresent invention relates to an improved process for preparing indanecarboxylates and cyclopentano[b]pyridine derivatives. Advantageously,the present invention relates to an improved process for preparing(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof and(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof. Such compounds aredescribed in International Application Number:PCT/US94/04603—International Publication Number WO 94/25013 published onNov. 10, 1994 and in U.S. Pat. No. 5,389,620, as being useful asendothelin receptor antagonists. Also invented are novel intermediatesuseful in preparing these compounds.

BACKGROUND OF THE INVENTION

[0002] Processes for the preparation of indane carboxylates,specifically(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid have previously been described. In particular a multistep processto prepare(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid in 6% overall yield (not including a racemic separation step) frommethyl 3-(prop-1-yloxy)benzoylacetate and a multistep process to prepare(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid in 2% overall yield (not including a racemic separation step) frommethyl 3-(prop-1-yloxy)benzoylacetate is reported in InternationalPublication Number WO 94/25013, published Nov. 10, 1994. The synthesesof these molecules are complicated by the presence of three chiralcenters in each compound.

[0003] Processes for the preparation of cyclopentano[b]pyridinederivatives have previously been described. In particular, multistepprocesses to prepare cyclopentano[b]pyridine derivatives, in low overall yield, are reported in U.S. Pat. No. 5,389,620.

[0004] Thus, there is a need in the art for an economical method toprepare indane carboxylates and cyclopentano[b]pyridine derivatives,specifically(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof and(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof.

[0005] The numerous advantages of the presently invented process andintermediates will become apparent upon review of the followingdescription.

SUMMARY OF THE INVENTION

[0006] This invention relates to an improved process for preparingaromatic ring-fused cyclopentane derivatives.

[0007] This invention also relates to novel intermediates useful inpreparing aromatic ring-fused cyclopentane derivatives.

[0008] This invention relates to an improved process for preparingindane carboxylates.

[0009] This invention also relates to novel intermediates useful inpreparing indane carboxylates.

[0010] This invention relates to an improved process for preparingcyclopentano[b]pyridine derivatives.

[0011] This invention also relates to novel intermediates useful inpreparing cyclopentano[b]pyridine derivatives.

[0012] This invention relates to an improved process for preparing(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof, preferably theethylene diamine 2:1 salt.

[0013] This invention relates to novel intermediates useful in preparing(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

[0014] This invention relates to an improved process for preparing(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof, preferably thedisodium salt.

[0015] This invention relates to novel intermediates useful in preparing(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

DETAILED DESCRIPTION OF THE INVENTION

[0016] Unless otherwise defined, the term ‘aromatic ring-fusedcyclopentane derivatives’ as used herein, is meant the racemic compoundsof Formula (1):

[0017] wherein A, B, C and D are carbon atoms or three of A, B, C and Dare carbon atoms and one is a nitrogen atom;

[0018] R¹ is

[0019] where R³ and R⁴ are independently H, OH, C₁₋₈alkoxy, F, CF₃ orC₁₋₆alkyl and R⁵ is —OCH₂CO₂H or —OCH₂CH₂OH;

[0020] R² is

[0021] where R³ and R⁴ are as indicated above and

[0022] Z is H, OH, or C₁₋₅alkoxy;

[0023] or a pharmaceutically acceptable salt thereof.

[0024] Preferred among the racemic compounds of Formula (1) are thecompounds of Formula (17):

[0025] wherein A, B, C, D, R¹, R² and Z are as described in Formula (1);

[0026] or a pharmaceutically acceptable salt thereof.

[0027] By the term indane carboxylates as used herein is meant theracemic compounds of Formula (2):

[0028] wherein R¹, R² and Z are as described in Formula (1);

[0029] or a pharmaceutically acceptable salt thereof.

[0030] Preferred among the racemic compounds of Formula (2) are thecompounds of Formula (18):

[0031] wherein R¹, R² and Z are as described in Formula (1);

[0032] or a pharmaceutically acceptable salt thereof.

[0033] By the term cyclopentano[b]pyridine derivatives as used herein ismeant the racemic compounds of Formula (3):

[0034] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom; and

[0035] R¹, R² and Z are as described in Formula (1);

[0036] or a pharmaceutically acceptable salt thereof.

[0037] Preferred among the racemic compounds of Formula (3) are thecompounds of Formula (19):

[0038] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom; and

[0039] R¹, R² and Z are as described in Formula (1);

[0040] or a pharmaceutically acceptable salt thereof.

[0041] In Formula (3) compounds, in Formula (19) compounds and inFormula (1) compounds when one of A, B, C or D is a nitrogen atom,preferably A is nitrogen.

[0042] Pharmaceutically acceptable salts of the compounds of Formulas(1), (2), (3), (17), (18) and (19) are formed where appropriate bymethods well known to those of skill in the art.

[0043] Pharmaceutically acceptable salts of(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop1-yloxy)indane-2-carboxylic acid and(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid are formed where appropriate by methods well known to those ofskill in the art.

[0044] By the term “Pr” as used herein is meant n-propyl.

[0045] By the term “Ph” as used herein is meant phenyl.

[0046] As used in the specification and in the claims, unless otherwisedefined, the term X_(c) means a chiral auxiliary. By the term “chiralauxiliary” as used herein is meant a non-racemic functional group thatimparts a diastereoselective reaction at a remote prochiral center of amolecule. Chiral auxiliaries as used herein are formed by reaction witha compound of the formula HX_(c) wherein X_(c) is as described above.Examples of HX_(c) as used herein include: 8-phenylmenthol (such asdescribed in D. Comins et al. J. Org. Chem., vol. 58, 4656 (1993)),N-substituted borane-2, 10-sultams (such as described in W. Oppolzer J.Am. Chem. Soc., 112 2767 (1990)), preferably, 4-substituted or4,5-substituted 2-oxazolidinones derived from amino acid derivativessuch as phenylglycinol or valinol (such as described in D. Evans et al.J. Am. Chem. Soc., 109, 6881 (1987) and in D. Evans et al. Tet. Lett.,28, 1123 (1990)) and, most preferably, 4-substituted or 4,5-substituted2-imidazolidinones derived from compounds such as ephedrine (such asdescribed in S. E. Drewes, et al. Chem. Ber., 126, 2663 (1993)). Themost preferred “X_(c)” for use herein is the predominately opticallypure substituent of the formula

[0047] Thus, the most preferred form of a chiral auxiliary for useherein is a compound of foumula (u):

[0048] Additionally, the racemic compounds of Formulas (1), (2) and (3)are prepared as described herein by substituting the chiral X_(C)substituent, as used herein, with an achiral group, such as an alkoxy oramine group.

[0049] The term ‘activation reaction’ for use herein refers to thenumerous reactions and reaction conditions known to those skilled in theart to effect the introduction of a Br, I, —OSO₂CF₃ or a —OSO₂Fsubstituent.

[0050] The term(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid as used herein utilizes standard chemical terminology and refers toCompound (r)

[0051] The term(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid ethylene diamine salt (2:1) as used herein utilizes standardchemical terminology and refers to Compound (s)

[0052] The term(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid as used herein utilizes standard chemical terminology and refers toCompound (j)

[0053] The term(+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid disodium salt as used herein utilizes standard chemical terminologyand refers to Compound (k)

[0054] The indane carboxylates of Formula (18) of the current inventionare prepared by methods outlined in the Schemes below and in theExamples from compounds of Formula (a);

[0055] where R is H, OH, C₁₋₅alkoxy (preferably n-PrO) or a protectedoxy group, such as benzyloxy. Compounds of Formula (a) are known or canbe prepared from readily available starting materials by those skilledin the art.

[0056] By the term ‘protected oxy group’ and ‘protected OH’ as usedherein, is meant any conventional blocking group in the art such asdescribed in “Protective Groups in Organic Synthesis” by Theodora W.Greene. Wiley-Interscience, 1981, New York, provided that such protectedoxy groups or such protected OH do not include moieties that renderinoperative the presently invented process. A preferred protected oxygroup for use herein is benzyloxy. A preferred protected OH for useherein is benzyloxy.

[0057] Further, when necessary or desired, R can be converted to asubstituent of Z. Reactions to convert R to Z are performed on productsof the synthetic pathways disclosed or claimed herein or, whereappropriate or preferable on certain intermediates in these syntheticpathways. For example, hydroxyl groups can be converted intoC_(l-5)alkoxy groups by alkylation. Protected oxy groups can bedeprotected and further reacted to form a substituent of Z.

[0058] The present invention provides an improved process for theproduction of indane carboxylates of Formula (18) as indicated inSchemes 1 and 2 below.

[0059] Scheme 1 outlines formation of indane carboxylates wherein R⁵ is—OCH₂CO₂H, preferably the disodium salt, Compound (k). As used in Scheme1, R³ and R⁴ are as described in Formula (1), R is as described inFormula (a) and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F. Compounds of Formula(c) are prepared in one or more steps by treating a compound of Formula(a) in an activation reaction, preferably with bromine in methylenechloride, to introduce substituent R⁷. Compounds of Formula (d) areprepared by reacting a compound of Formula (c) with an acid chloride,such as thionyl chloride, and using this product as an acylating agentin a reaction, such as a Grignard reaction with a compound of Formula(t) as defined on page 32, or a Friedel-Crafts reaction, such asdescribed in Example 1, step (iii). Compounds of Formula (e) areprepared by reacting a compound of Formula (d) with a chiral auxiliaryin the presence of palladium(II) acetate/triphenylphosphine catalyst.Treatment of a compound of Formula (e) with an appropriately substituted3,4-(methylenedioxy)phenylmagnesium bromide (which can be readilyprepared from commercially available starting materials) and a coppercomplex, such as copper(I) bromide-dimethylsulfide complex (which iscommercially available from the Aldrich Chemical Co. of Milwaukee,Wis.), in tetrahydrofuran followed by crystallization gives compounds ofFormula (f) as the predominately pure diastereomer. Treatment of acompound of Formula (f) with sodium methoxide/methanol gives compoundsof Formula (g). Compounds of Formula (h) are prepared by treating acompound of Formula (g) in methanol with anhydrous acid. Compounds ofFormula (i) are prepared by hydrogenating a compound of Formula (h) overpalladium on carbon. Treating a compound of Formula (i) with methylbromoacetate and potassium carbonate in acetone/methanol, followed bysaponification/epimerization effected with lithium hydroxide monohydrateand acid workup yields the corresponding diacid of Formula (6)(preferably Compound (j) as used herein). Compounds of Formula (6) aretreated with sodium hydroxide to give compounds of Formula (4)(preferably Compound (k) as used herein). Additionally, treating acompound of Formula (i) with ethylene carbonate/potassium carbonate intoluene at 90-115° C. followed by saponification/epimerization withlithium hydroxide and acidic work up is a preferred method for preparinga compound of Formula (7). It is readily apparent to those of skill inthe art that the substituent —OCH₂Ph in the above Scheme is functioningas a protected OH and that another protected OH group could be utilizedin its place or that, under appropriate circumstances, the unprotectedOH could be utilized.

[0060] Scheme 2 outlines formation of indane carboxylates wherein R⁵ is—OCH₂CH₂OH, preferably the ethylene diamine salt (2:1), Compound (s). Asused in Scheme 2, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F. The acidchloride of the compounds of Formula (c) from Scheme 1 are reacted in anacylation reaction, preferably in a Grignard reaction with a compound ofFormula (v) prepared as described on page 33, to give compounds ofFormula (1). Compounds of Formula (m) are prepared by reacting acompound of Formula (1) with a chiral auxiliary in the presence ofpalladium(II) acetate/triphenylphosphine catalyst. Treatment of acompound of Formula (m) with an appropriately substituted3,4-(methylenedioxy)phenylmagnesium bromide (which can be readilyprepared from commercially available starting materials) and a coppercomplex, preferably a copper (I) salt such as CuCl, CuBr, CuCN or mostpreferably copper(I) bromide-dimethylsulfide complex (which iscommercially available from the Aldrich Chemical Co. of Milwaukee, Wis.)in tetrahydrofuran gives compounds of Formula (n) as the predominatelypure diastereomer. Treatment of a compound of Formula (n) with sodiummethoxide/methanol gives compounds of Formula (o). Compounds of Formula(p) are prepared by treating a compound of Formula (o) in methanol withanhydrous acid. Compounds of Formula (q) are prepared by hydrogenatingcompounds of Formula (p) over palladium on carbon. Treatment ofcompounds of Formula (q) with lithium hydroxide monohydrate followed byacidic workup gives the acid of Formula (7) (preferably Compound (r) asused herein). Compounds of Formula (7) are treated with ethylene diamineto give compound of Formula (8) (preferably Compound(s) as used herein).It is readily apparent to those of skill in the art that the substituent—OCH₂Ph in the above Scheme is functioning as a protected OH and thatanother protected OH group could be utilized in its place or that, underappropriate circumstances, the unprotected OH could be utilized.

[0061] The racemic compounds of Formulas (1), (2) and (3) are preparedaccording to the methods outlined in Schemes (1) and (2) and in theExamples by substituting a compound of Formula (9):

[0062] wherein A, B, C and D are carbon atoms or three of A, B, C and Dare carbon atoms and one is a nitrogen atom and

[0063] R is H, OH, C₁₋₅alkoxy (preferably n-PrO) or a protected oxygroup, such as benzyloxy,

[0064] for the compound of Formula (a) and by substituting the chiralX_(C) substituent of the chiral auxiliary with an achiral group, such asan alkoxy or amine group.

[0065] Compounds of Formula (9) are known or can be prepared fromreadily available starting materials by those skilled in the art.

[0066] Thus, an achiral group is substituted for the X_(C) substituentof the chiral auxiliary in Schemes 1 and 2 to prepare compounds ofFormula (2) and intermediates useful in preparing compounds of Formula(2). The compounds of Formula (9) are utilized in Schemes 1 and 2, bysubstituting the chiral X_(C) substituent of the chiral auxiliary withan achiral group, to prepare compounds of Formula (1) and intermediatesuseful in preparing compounds of Formula (1). The compounds of Formula(9), wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, are utilized in Schemes 1 and 2, by substituting thechiral X_(C) substituent of the chiral auxiliary with an achiral group,to prepare compounds of Formula (3) and intermediates useful inpreparing compounds of formula (3).

[0067] The cyclopentano[b]pyridine derivatives of Formula (19) of thecurrent invention are prepared according the methods outlined in Schemes1 and 2 and in the Examples from compounds of Formula (9) wherein threeof A, B, C and D are carbon atoms and one is a nitrogen atom. Preferredamong Formula (9) compounds when a nitrogen is present are those whereinA is nitrogen.

[0068] The aromatic ring-fused cyclopentane derivatives of Formula (17)of the current invention are prepared according the methods outlined inSchemes 1 and 2 and in the Examples from compounds of Formula (9)wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom. Preferred among Formula (9)compounds when a nitrogen is present are those wherein A is nitrogen.

[0069] Prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (k) and Compound (s), are novel intermediates ofFormula (c):

[0070] wherein R is as described in Formula (a) and R⁷ is Br, I,—OSO₂CF₃ or —OSO₂F.

[0071] Also prepared in synthesizing the indane carboxylates of Formula(18), preferably Compound (k) and Compound (s), are novel intermediatesof the formula:

[0072] wherein R is as described in Formula (a) and R⁷ is Br, I,—OSO₂CF₃ or —OSO₂F.

[0073] Also prepared in synthesizing the indane carboxylates of Formula(18), preferably Compound (k), are novel intermediates of Formula (d):

[0074] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a), R⁶ is OH or a protected OH and R⁷ is Br, I,—OSO₂CF₃ or —OSO₂F.

[0075] Also prepared in synthesizing the indane carboxylates of Formula(18), preferably Compound (k), are novel intermediates of Formula (e):

[0076] wherein R³ and R⁴ are as described in Formula (1), X_(C) is asdescribed above, R is as described in Formula (a) and R⁶ is OH or aprotected OH.

[0077] Also prepared in synthesizing the indane carboxylates of Formula(18), preferably Compound (k), are novel intermediates of Formula (f):

[0078] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0079] Also prepared in synthesizing the indane carboxylates of Formula(18), preferably Compound (k), are novel intermediates of Formula (g):

[0080] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0081] Also prepared in synthesizing the indane carboxylates of Formula(18), preferably Compound (k), are novel intermediates of Formula (h):

[0082] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0083] Prepared in synthesizing the indane carboxylates of Formula (2),preferably Compound (k), are novel racemic intermediates of Formula(27):

[0084] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0085] Also prepared in synthesizing the indane carboxylates of Formula(18), preferably Compound (k) and Compound (s), are novel intermediatesof Formula (i):

[0086] wherein R³ and R⁴ are as described in Formula (1) and R is asdescribed in Formula (a).

[0087] Prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (s), are novel intermediates of Formula (1):

[0088] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a), R⁶ is OH or a protected OH and R⁷ is Br, I,—OSO₂CF₃ or —OSO₂F.

[0089] Also in synthesizing the indane carboxylates of Formula (18),preferably Compound (s), are novel intermediates of Formula (m):

[0090] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0091] Also in synthesizing the indane carboxylates of Formula (18),preferably Compound (s), are novel intermediates of Formula (n):

[0092] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0093] Also in synthesizing the indane carboxylates of Formula (18),preferably Compound (s), are novel intermediates of Formula (o):

[0094] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0095] Also in synthesizing the indane carboxylates of Formula (18),preferably Compound (s), are novel intermediates of Formula (p):

[0096] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0097] Also in synthesizing the indane carboxylates of Formula (2),preferably Compound (s), are novel racemic intermediates of Formula(28):

[0098] wherein R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or a protected OH.

[0099] Also in synthesizing the indane carboxylates of Formula (18),preferably Compound (s), are novel intermediates of Formula (q):

[0100] wherein R³ and R⁴ are as described in Formula (1) and R is asdescribed in Formula (a).

[0101] Prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (I) are novel intermediates of Formula (10):

[0102] wherein A, B, C and D are carbon atoms or three of A, B, C and Dare carbon atoms and one is a nitrogen atom and R is as described inFormula (a).

[0103] Prepared in synthesizing the cyclopentano[b]pyridine derivativesof Formula (19) are intermediates of Formula (10) where three of A, B, Cand D are carbon atoms and one is a nitrogen atom and R is as describedin Formula (a).

[0104] Prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are novel intermediates of Formula (11):

[0105] wherein A, B, C and D are carbon atoms or three of A, B, C and Dare carbon atoms and one is a nitrogen atom, R is as described inFormula (a) and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F.

[0106] Prepared in synthesizing the cyclopentano[b]pyridine derivativesof Formula (19) are intermediates of Formula (11) where three of A, B, Cand D are carbon atoms and one is a nitrogen atom, R is as described inFormula (a) and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F.

[0107] Prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are novel intermediates of the Formula:

[0108] wherein A, B, C and D are carbon atoms or three of A, B, C and Dare carbon atoms and one is a nitrogen atom, R is as described inFormula (a) and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F.

[0109] Prepared in synthesizing the cyclopentano[b]pyridine derivativesof Formula (19) are intermediates of the preceding compound where threeof A, B, C and D are carbon atoms and one is a nitrogen atom, R is asdescribed in Formula (a) and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F.

[0110] Also prepared in synthesizing the cyclopentano[B]pyridinederivatives of Formula (19) are the novel intermediates of Formula (12):

[0111] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a), R⁶ is OH or protected OH and R⁷ is Br, I,—OSO₂CF₃ or —OSO₂F.

[0112] Also prepared in synthesizing the cyclopentano[B]pyridinederivatives of Formula (19) are the novel intermediates of Formula (13):

[0113] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, X_(C) is as described above, R³ and R⁴ are as describedin Formula (1), R is as described in Formula (a) and R⁶ is OH orprotected OH.

[0114] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel intermediates of Formula (14):

[0115] wherein three A, B, C and D are carbon atoms and one is anitrogen atom, X_(C) is as described above, R³ and R⁴ are as describedin Formula (1), R is as described in Formula (a) and R⁶ is OH orprotected OH.

[0116] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel intermediates of Formula (15):

[0117] wherein three A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or protected OH.

[0118] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel intermediates of Formula (16):

[0119] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or protected OH.

[0120] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel racemic intermediates ofFormula (29):

[0121] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or protected OH.

[0122] Also prepared in synthesizing the cyclopentano[B]pyridinederivatives of Formula (19) are the novel intermediates of Formula (20):

[0123] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1) and R is asdescribed in Formula (a).

[0124] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel intermediates of Formula (21):

[0125] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a), R⁶ is OH or protected OH and R⁷ is Br,1,—OSO₂CF₃ or —OSO₂F.

[0126] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel intermediates of Formula (22):

[0127] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, X_(C) is as described above, R³ and R⁴ are as describedin Formula (1), R is as described in Formula (a) and R⁶ is OH orprotected OH.

[0128] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel intermediates of Formula (23):

[0129] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, X_(C) is as described above, R³ and R⁴ are as describedin Formula (1), R is as described in Formula (a) and R⁶ is OH orprotected OH.

[0130] Also prepared in synthesizing the cyclopentano[B]pyridinederivatives of Formula (19) are the novel intermediates of Formula (24):

[0131] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or protected OH.

[0132] Also prepared in synthesizing the cyclopentano[β]pyridinederivations of Formula (19) are the novel intermediates of Formula (25):

[0133] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or protected OH.

[0134] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel racemic intermediates ofFormula (30):

[0135] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1), R is asdescribed in Formula (a) and R⁶ is OH or protected OH.

[0136] Also prepared in synthesizing the cyclopentano[β]pyridinederivatives of Formula (19) are the novel intermediates of Formula (26):

[0137] wherein three of A, B, C and D are carbon atoms and one is anitrogen atom, R³ and R⁴ are as described in Formula (1) and R is asdescribed in Formula (a).

[0138] Prepared in synthesizing the compounds of this invention arenovel intermediates of the predominantly optically pure compound:

[0139] Prepared in synthesizing the compounds of this invention arenovel intermediates of the predominantly optically pure compound:

[0140] All of the starting materials and reagents used herein are knownand readily available or can be easily made from known and readilyavailable reagents.

[0141] For example, compound (t) is prepared according to the followingsteps (as used below R³ and R⁴ are as described in Formula (1)):

[0142] a) an appropriately substituted 2-Bromo-5-methoxyphenol, preparedby methods such as described in de Paulis, et al. J. Med. Chem., 28,1236 (1985), is treated with benzyl bromide and potassium carbonate toform the compound

[0143] b) treating the product of step a) with magnesium intetrahydrofuran to form the compound

[0144] For example, compound (v) is prepared according to the followingsteps:

[0145] c) treating an appropriately substituted 2-Bromo-5-methoxyphenolfrom step a) above with ethylene carbonate and potassium carbonate intoluene to form the compound

[0146] d) treating the product of step c) with potassium carbonate andbenzyl chloride in N,N-dimethylformamide to form compound

[0147] e) treating the product of step d) with magnesium intetrahydrofuran to form compound

[0148] For example, the most preferred compound (u) is preparedaccording to the following steps:

[0149] e) commercially available (1R,2S)-(−)-ephedrine hydrochloride isreacted with urea and heat to form the compound

[0150] f) treating the product of step e) with acroyl chloride in thepresence of base to form compound (u). Preferably, the product of stepe) is reacted in the presence of 3-chloropropionyl chloride and a baseto form the predominantly optically pure compound (u)

[0151] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following Examples are, therefore,to be construed as merely illustrative and not a limitation of the scopeof the present invention in any way.

EXAMPLES Example 1 Corresponding to Scheme 1(+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicAcid Disodium Salt

[0152]

[0153] (a compound of Formula (a))

[0154] A 12 L 3-necked flask was changed with 500 g (3.62 mol) of3-hydroxybenzoic acid, 4 L of acetonitrile and 435 g (10.88 mol) ofsodium hydroxide in 1.1 L of water. Heated the resulting mix to 60° C.over 40 minutes. Over a 60 minute period the n-dipropyl sulphate (2.5eq) was added via an addition funnel while maintaining the reactiontemperature 65-70° C. After 6 hours a second portion of sodium hydroxidein 1.0 L of H₂O was added over 30 minutes within 65-70° C. After another1.0 L at 65-70° C. the acetonitrile was allowed to evaporate to one halfits original volume. 1.0 L of water was added and the pH was adjusted to3.0 using 850 mL of conc. HCl. 7 L of ethyl acetate was added and themixture allowed to stir 30 minutes at ambient temperature. At this timethe reaction mixture was transferred to a 22 L separatory funnel and 1 Lwater was added to dissolve inorganic particulates. The organic layerwas separated and the organic washed with water (2×4 L) and brine (1×4L). The solvent was removed until only 600-700 mL remained. 700 mL ofhexanes was added and the solution was cooled to 0-5° C. for 3 hours.The solid that precipitated was filtered assay 274 g (1.52 mol). Asecond crop of 254 g (1.41 mol) was obtained for a total yield of theabove depicted compound of 81%; mp 69-71° C.

[0155] (a compound of Formula (c))

[0156] A 22 L, 3-necked flask was charged with 1.037 kg (5.70 mol) ofthe compound from step (i), 14.2 L of methylene chloride and 579 g ofsodium acetate. To this stirred solution was slowly added bromine,keeping the temperature below 34° C. Bromine (1.15 eq) was added untilthe dark reddish-brown bromine color persisted. Reaction was deemedcompleted when HPLC monitoring showed starting material was <1.5%. 1.0 Lof water and 60 g of sodium bisulfite was added. The solvent was removeduntil the reaction volume was ˜3.0 L. 4 L of ethyl acetate was added andthe reaction volume was reduced to 2.5-3 L. 6 L of ethyl acetate wasadded and the pH was adjusted to ˜2 using 300 mL of 50% conc. HCl (v/v).2 L of water was added the organic layer was separated. The aqueouslayer was washed with water (1×4 L) and brine (1×3 L). The solution wasreduced to 2 L where upon a white slurry resulted. 800 mL of hexanes wasadded and the flask was cooled at 0-5° C. for 3 hours with stirring. Thesolid was collected by filtration to yield the above depicted compound(1171.8 g, 4.5 mol). A second crop was obtained, 189.8 g (0.73 mol) fora total of 5.23 mol, 91% yield; mp 100-102° C.

[0157] (a compound of Formula (d))

[0158] A 3 L, 3-necked flask was charged with 1 kg (3.86 mol) of thecompound from step (ii) and thionyl chloride (114.7, 700 mL, 9.62 mol,2.49 eq) was added all at once. Mixing is endothermic and the reactiontemperature drops to 12° C. The slurry is heated to 20-30° C. for 5 and3/4 hours or until the HPLC indicates the disappearance of startingmaterial. The reaction mixture is cooled to ambient temperature and 1 Lof toluene is added. The reaction mixture is concentrated by vacuumdistillation to about 700 mL and an additional 500 mL toluene was added.Vacuum distillation was continued until 250 mL of toluene was collected.

[0159] A 12 L 3-necked flask was charged with the above solution (assume3.86 mol) and 1,3-dimethoxybenzene (533 g, 3.86 mol). The subsequentsolution was cooled to 10° C. and placed under nitrogen atmosphere.Boron trichloride (1 m soln in xylene, 4.2 L, 4.2 mol, 1.088 eq) wasadded at such a rate that the temperature did not exceed 16° C. Additiontakes place over 4 hours, the reaction being 91% complete after additionis complete. The reaction mixture is stirred an additional hour, chilledto 10° C. with an ice bath and quenched carefully with 3 L of water,keeping the temperature below 15° C. The reaction slurry is then heatedto 50° C. to dissolve all solids, transferred to a separatory funnel andthe organic phase separated, washed with 2×2 L H₂O, 1 L 50% brine. Theorganic solubles are concentrated in vacuo and chased with hexane toproduce a crude solid which is recrystallized from 2800 mL 190 proofEtOH. Yield 1202.8 g of the 4-methoxy-2-hydroxy precursor of the titlecompound (85%, HPLC purity, 97.0% by area).

[0160] In a 3 L, 3-necked flask was added 1.5 L of acetonitrile, theabove 4-methoxy-2-hydroxy precursor (277.4 g, 0.76 mol), and 214.4 g(1.55 mol) of K2CO3. At room temperature under nitrogen was added benzylbromide (132.6 g, 0.76 mol). The reaction was heated to reflux (80-81°C.) for 2-4 hours and was followed by HPLC for disappearance of thestarting material. The reaction mixture was then cooled to 50° C. andfilled to remove inorganics. The solvent was removed under vacuum toyield the above depicted compound as a white solid; 347.0 g (0.762 mol);mp 46-51° C.; yield 100%.

[0161] (a compound of Formula (e))

[0162] In a 12 L, 3-necked flask was added 600.0 g (1.316 mol) of thecompound from step (iii) 312 g of compound (u) (preparation of compound(u) as used in this example is described in the specification on page 33and in Example 4), 7.4 g of palladium acetate (0.033 mol) 20.2 g oftri-o-tolylphosphine (0.066 mol) 3.3 L of DMF and 107.9 (1.316 mol) ofsodium acetate. The reaction mixture was degassed with nitrogen thenheated to 135-140° C. The reaction was monitored by HPLC for thedisappearance of starting material. The reaction mixture was cooled to115° C. where 2 L of water and 2 L of toluene were carefully added. Thesolution was allowed to stir for 7 hours under nitrogen. The reactionsolution was warmed to 40-45° C. H₂O (3.3 L) and toluene (3.3 L) wasadded at 50° C. then transferred warm to a 12 L separatory funnel. Theseparate organic layer was separated and the aqueous layer was washedwith water (2×3.3 L). The organic layer was concentrated to yield a wetsolid. This material was dissolved in 3.2 L of 190 ethanol. Thissolution was cooled to 0-5° C. The precipitated solids were collectedvia filtration to yield 586 g (0.95 mol, 72%) of the above depictedcompound.

[0163] a) compound of Formula (f))

[0164] A 3-necked 250 ml flask was charged with cuprous bromide dimethylsulphide complex (319 g, 019 mol) in 5 mL of THF/Dimethyl sulphide (3/1ratio v/v). The suspension was cooled to −35° C. and the Grignard (0.04mol) was added at that temperature. The dark brown suspension wasallowed to warm to −5° C. and stir 2-3 minutes then was cooled back downto -35° C. After a total stir time of 35 minutes, the compound from step(iv) (10.0 g, 0.016 mol) dissolved in THF (33 mL) was added over 30minutes. The reaction was stirred at −35° C. for 2 hours and at −10° C.for one hour. Aqueous ammonium acetate (100 mL of saturated solution)was added at 0° C. and the suspension was stirred at ambient temperature30 minutes. The organic layer was separated and the aqueous layer wasextracted with t-butyl methyl ether (3×100 mL). The combined organiclayer was washed with ammonium hydroxide (25% solution) until the bluecolor no longer persisted. The solvent was removed under vacuum and 50mL toluene was added then was also removed under vacuum. The residualoil was dissolved in 50 mL of IPA and 150 mL of hexanes was added. Thesolution was allowed to stir 18 hours at which time a suspensionresulted. An additional 150 mL of hexanes was added and the flask wascooled to 0° C. and stirred 30 minutes then filtered. The solid productwas dried under vacuum to yield the above depicted compoundpredominately as the single diastereomer; mp 164-166° C.; 9.72 g (0.013mol, 81% yield).

[0165] (a compound of Formula (h))

[0166] A 2.0 L, 3-necked round-bottomed flask was charged with 1.5 L oftoluene and 80.0 g (0.108 mol) of the compound of step (v). The solutionwas heated to reflux until ˜700 mL of solution remained. The solutionwas then allowed to cool to room temperature under nitrogen. Sodiummethoxide 3.0 eq as a 25% solution was slowly added over 10 minutes. Thesolution was allowed to stir until <1.0% of starting material remainedby HPLC. The reaction mixture was cooled to −20° C. then diluted with200 mL of methanol. The this solution was added 4.5 eq of acetylchloride (neat) dropwise over 15 minutes keeping the reactiontemperature at −10° C. The reaction mixture was allowed to warm to roomtemperature and stir 1 Hour. It was then diluted with 200 mL TBME and500 mL of water with vigorous stirring. The organic layer was removed(pH=1) and washed with 20% ethanol (3×600 mL) to remove the chiralauxiliary and yield the above depicted compound predominately as thesingle enantiomer.

[0167] (a compound of Formula (i))

[0168] A 150 mL ethyl acetate solution of the compound of step (vi) (30.g; 0.053 mol) was diluted with 100 mL of methanol. To this solution wasadded 4.0 g of palladium hydroxide on carbon followed by 0.5 mL ofconcentrated HCl to pH 2-3. The reduction vessel was pressurized to 75psi and kept ˜1.5 hours or until HPLC indicated the disappearance of thestarting material. The reaction was filtered and concentrated to yield18 g (70% yield) of the above depicted compound predominately as thesingle enantiomer.

[0169] (a compound of Formula (k))

[0170] A 5 L 3 necked round-bottom flask equipped with an air drivenstirrer, and a nitrogen inlet/outlet was charged with 212.0 g (98.4%wt/wt, 437.8 mmol) of the compound of step (vii), 2120 mL of acetone and212 mL of methanol. The resulting slurry/solution was degassed forapproximately 10 minutes under house vacuum. After releasing the vacuumand flushing the flask with nitrogen, 302.5 g (2.19 moles) of potassiumcarbonate followed by 87.1 g (546.6 mmol) of methyl bromoacetate wereadded in single portions. The resulting slurry was stirred at ambienttemperature under an atmosphere of nitrogen while the progress of thereaction was monitored by HPLC. The reaction was deemed to be completewhen all the starting material had been converted to the title compound.The slurry was filtered through 300 g of Aluminium oxide rinsing with1250 mL of acetone. The resulting filtrate was concentrated underreduced pressure to a volume of approximately 500 mL. The concentratewas diluted with 2000 mL of t-butyl methyl ether (TBME) then washed with2×1000 ml portions of 5% aqueous citric acid followed by 1000 mL ofsaturated aqueous brine to afford 1720 g of(+)-methyl-(1S,2S,3S)-5-propoxy-1-(3,4-methylenedioxy-phenyl)-3-(2-carbomethoxy]methoxy-4-methoxyphenyl)indane-2-carboxylate(the cis alkylated diester intermediate to the above depicted compound)as a solution in TBME. Analysis indicated 15.6% wt/wt and 98.5% PAR byHPLC. An analytical sample could be obtained by crystallization of aconcentrate from a mixture of hexane's and TBME.

[0171]¹H NMR (CDCl₃), δ 7.36 (d, 1H), 7.07 (d, 1H), 6.73-6.88 (m, 5H),6.49 (q, 1H), 6.37 (d, 1H), 5.94 (s, 2H), 5.17 (d, 1H), 4.684.74 (m,3H), 4.02 (t, 1H), 3.90 (t, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 2.97 (s,3H), 1.75-1.87 (m, 2H), 1.0 (t, 3H ) ppm.

[0172] Saponification/epimerization of(+)-methyl-(1S,2S,3S)-5-Propoxy-1-(3,4methylenedioxy-phenyl)-3-(2-carbomethoxy]methoxy-4-methoxyphenyl)indane-2-carboxylateto(+)-(1S,2R,3S)-5-Propoxy-1-(3,4-methylenedioxy-phenyl)-3-(2-carbomethoxy]methoxy-4-methoxyphenyl)indane-2-carboxylicacid was effected by concentration of the TBME solution, dilution with2-propanol and water and subsequent treatment with an excess of 50%aqueous sodium hydroxide solution (25 equivalents). When thesaponification/epimerization was deemed complete, the mixture wasacidified with 6N aqueous HCl. Subsequent extractive work-up affordedthe diacid intermediate of title compound as a solution in TBME.Treatment of the diacid with sodium hydroxide afforded the abovedepicted compound predominately as the single enantiomer.

Example 2 Corresponding to Scheme 2(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicAcid Ethylene Diamine Salt (2:1)

[0173] (i) The title compound was prepared according to Example 1, steps(i) to (vii) by substituting1-bromo-4-methoxy-2-(2-benzyloxy)ethoxybenzene for 1,3-dimethoxybenzenein step (iii) and utilizing a Grignard reaction in place of theFriedel-Crafts conditions of step (iii) to prepare the mono ester ofcompound (q), as described in Scheme 2. Saponification/epimerization ofthe mono ester with lithium hydroxide in THF afforded the free acid,compound (r) as described on page 7. Compound (r) was treated withethylene diamine to afford title compound.

Example 3 Corresponding to Scheme 1(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicAcid Ethylene Diamine Salt (2:1)

[0174] (i) A 500 mL flask was charged with 150 mL of toluene followed byethylene carbonate (29.4 g, 98%, 327 mmol) and 15.9 g (97.4%, 32.6 mmol)ofmethyl-(1S,2S,3S)-1-(3,4methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylate(a compound of Formula (i) prepared as in step (vii) of Example 1). Withmoderate agitation at ambient temperature, potassium carbonate (23.1 g,98%, 163.8 mmol) was added. Under an atmosphere of nitrogen and withmoderate agitation, the contents of the flask were heated toapproximately 112° C. After approximately 3 hours at or around 112° C.,the reaction was cooled to 25-30° C. over a period of 20 minutes, and DIwater (120 mL) was added. The mixture was stirred then the aqueous layerwas separated. The organic phase was concentrated to a gum under reducedpressure then diluted with methanol (50 mL) and tetrahydrofuran (80 mL).A solution of lithium hydroxide monohydrate, 4.5 g (477.8 mmol)dissolved in 50 mL of water was then added. The reaction mixture washeated to reflux (internal temperature 62-65° C.) over approximately 15minutes and maintained at reflux while monitoring the reaction progressby HPLC. The reaction was considered complete when no intermediates weredetected by HPLC analysis. After approximately 60 minutes at reflux thereaction was considered complete and the contents of the flask cooled toambient and the reaction mixture concentrated under reduced pressure.Toluene (150 mL), water (150 mL) followed by citric acid (15 g) was thenadded to the resulting solution and the mixture stirred forapproximately 15 minutes. The bottom aqueous layer was drained and theorganic layer was washed with aqueous brine solution (100 mL). Theorganic layer was drained from the flask, then concentrated in vacuo toafford 16.2 g of the free acid of the title compound as a foam.

[0175] HPLC wt/wt assay indicated 90.5% purity for a corrected yield of88.8%.

[0176] An analytical sample could be obtained by recrystallization from2-propanol. Mpt. 125-127° C.

[0177] (ii) A toluene solution of(+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (868.8 g @ 11.2% wt/wt, 192.5 mmol) was concentrated under reducedpressure to a volume of approximately 200 mL. Distillation wasdiscontinued and 2-propanol (500 mL) added to the concentrate. Theorganic solution was concentrated again under reduced pressure to avolume of approximately 200 mL. Distillation was discontinued and2-propanol (500 mL) added to the concentrate. The resulting solution in2-propanol was allowed to stir at ambient temperature for approximately15 minutes to obtain a homogeneous mixture then diluted with anadditional 1000 mL of 2-propanol. The resulting solution was heated toapproximately 60° C. over a period of 15-20 minutes under a gentle purgeof nitrogen. Heating was discontinued and ethylene diamine (11.6 g,99.5+%, 192.5 mmol) was added. The reaction mixture was cooled to 30-35°C. over a period of 4 hours. As the solution cooled to 57° C.,precipitation of the title compound occurred. The resulting slurry wasstirred at ambient temperature for approximately 12 hours then cooled to0° C. an additional 3 hours before isolation of the title compound viafiltration. The product was washed with 3 portions of 2-propanol (300mL) followed by hexane's (600 mL) chilled to 0-5° C. The product wasdried in the vacuum oven for approximately 16 hours at 20-25° C. toafford 91.6 (87%) of the title compound.

[0178] Anal Calcd. for C30H34NO8 C, 67.15; H, 6.39; N, 2.61. Found, C,67.2; H, 6.48; N, 2.67.

Example 4 Chiral Auxiliary

[0179]

[0180] L-ephedrine hydrochtride

[0181] To a 3-necked, 12 L round-bottomed flask was charged 5 L oftoluene and ephedrine hydrochloride (1.625 hg, 8.06 mol). The flask washeated to 110° C. with mechanical stirring while the solution was beingcontinually purged with nitrogen. Toluene was distilled away using adistillation condenser and the solution was heated to 164-170° C. for 3hours. HPLC showed the disappearance of most of the product so thereaction mixture was allowed to cool to 120° C. where 4 L of water wasadded. The mixture was stirred and allowed to cool to room temperatureand was filtered. The white solid product was dissolved in 2 L ofacetonitrile and concentrated to near dryness where most of the solidproduct crystallized from solution. The flask was stored in therefrigerator over night at 0° C. The solid was filtered and washed with15% acetonitrile/water (1 L) and dried in vacuo at 60° C. for 24 hours.The above depicted predominately optically pure compound was obtained asa white solid: 664.8 g (43.4% yield); mp 177-179° C.

[0182] A 5 L, 3-necked flask was charged with 300 g (1.54 mol) of thecompound of step i), 3-chloropropionyl chloride (200 mL) and 3 L ofacetonitrile. The solution was heated at 75° C. for 8 hours then allowedto cool to room temperature. Potassium carbonate (435 g, 3.15 mol, 2equiv) was added and the suspension was again heated to 75° C. for 7hours. The reaction mixture was then cooled to room temperature andfiltered. The solvent was removed in vacuo and 680 mL of n-propanol wasadded and the solvent was cooled to 0° C. and held there for 1 hour. Theabove depicted predominately optically pure compound was isolated byfiltration, washed with hexanes (150 mL), and dried: 326 g (85% yield);mp 149.5-151.0° C.

[0183] While the preferred embodiments of the invention are illustratedby the above, it is understood that the invention is not limited to theprecise instructions herein disclosed and that the right to allmodifications coming within the scope of the following claims isreserved.

What is claimed is:
 1. A process for the preparation of the racemicmixture of compounds of Formula (1):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom; R¹ is

where R³ and R⁴ are independently H, OH, C₁₋₈alkoxy, F, CF₃ or C₁₋₆alkyland R⁵ is —OCH₂CO₂H; R² is

where R³ and R⁴ are as indicated above and Z is H, OH, or C₁₋₅alkoxy; ora pharmaceutically acceptable salt thereof, which comprises the stepsof: (1) treating a compound of Formula (10):

where A, B, C and D are as described above; and R is H, OH, C₁₋₅alkyl ofa protected oxy group, in an activation reaction to form a compound offormula (11):

where A, B, C, D and R are as described above and R⁷ is Br, I, —OSO₂CF₃or —OSO₂F; (2) reacting the product of step (1) with an acid chloride toform a compound of the formula

where A, B, C, D, R and R⁷ are as defined above; and a compound of theFormula:

where R³ and R⁴ are as described above, R⁶ is OH or protected OH and R⁸is MgBr or H, to form a compound of Formula (12):

where A, B, C, D, R. R³, R⁴ and R⁶ as defined above and R⁷ is Br, I,—OSO₂CF₃ or —OSO₂F; (3) reacting the product of step (2) with thecompound

wherein X_(C) is an achiral group; in the presence of a catalyst to forma compound of formula (13):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (4)treating the product of step (3) with a compound of the formula:

where R³ and R⁴ are as defined above, with copper complex to form acompound of the Formula:

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (5)treating the product of step (4) with sodium methoxide in methanol toform a compound of the Formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (6) treatingthe product of step (5) under acidic conditions to form a compound ofthe Formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (7)hydrogenating the product of step (6) over palladium to form a compoundof Formula (29):

where A, B, C, D, R, R³ and R⁴ are as defined above; (8) treating theproduct of step (7) with methyl bromoacetate, potassium carbonate inacetone/methanol, followed by saponification with lithium hydroxidemonohydrate and acidic workup to form a compound of the Formula:

where A, B, C, D, R, R³ and R⁴ are as defined above; (9) treating theproduct of step (8) with sodium hydroxide to form the final product, thecompound

where A, B, C, D, R, R³ and R⁴ are as defined above.
 2. A process forthe preparation of the racemic mixture of compounds of Formula (1):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom; R¹ is

where R³ and R⁴ are independently H, OH, C₁₋₈alkoxy, F, CF₃ or C₁₋₆alkyland R⁵ is —OCH₂CH₂OH; R² is

where R³ and R⁴ are as indicated above and Z is H, OH, or C₁₋₅alkoxy; ora pharmaceutically acceptable salt thereof, which comprises the stepsof: (1) reacting the compound (11):

where A, B, C and D are as described above, R is H, OH, C₁₋₅alkyl of aprotected oxy group and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F; with an acidchloride to form a compound of the formula

where A, B, C, D, R and R⁷ are as defined above, and a compound of theformula:

where R³ and R⁴ are as described above, R⁶ is OH or protected OH and R⁸is MgBr, to form a compound of Formula (21)

where A, B, C, D, R, R³, R⁴ and R⁶ are as described above and R⁷ is Br,I, —OSO₂CF₃ or —OSO₂F; (2) reacting the product of step (1) with thecompound

wherein X_(C) is an achiral group; in the presence of a catalyst to forma compound of formula (22):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (3)treating the product of step (2) with a compound of the formula:

where R³ and R⁴ are as defined above, with copper complex to form acompound of the Formula:

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (4)treating the product of step (3) with sodium methoxide in methanol toform a compound of the Formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (5) treatingthe product of step (4) under acidic conditions to form a compound ofthe Formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (6)hydrogenating the product of step (5) over palladium to form a compoundof Formula:

where A, B, C, D, R, R³ and R⁴ are as defined above; (7) treating theproduct of step (6) with lithium hydroxide monohydrate to effectsaponification and epimerization followed by acidic workup to form acompound of the Formula:

where A, B, C, D, R, R³ and R⁴ are as defined above; (8) treating theproduct of step (7) with ethylene diamine to form the final product, thecompound

where A, B, C, D, R, R³ and R⁴ are as defined above.
 3. A compound ofFormula (11):

where A, B, C, D, R and R⁷ are as defined in claim
 1. 4. A compound ofthe Formula:

where A, B, C, D, R and R⁷ are as defined in claim
 1. 5. A compound ofFormula (12):

where A, B, C, D, R, R³, R⁴, R⁶ and R⁷ are as defined in claim
 1. 6. Acompound of Formula (13):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined in claim
 1. 7.A compound of the Formula:

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined in claim
 1. 8.A compound of the Formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim
 1. 9. Acompound of the Formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim
 1. 10. Acompound of the Formula:

where A, B, C, D, R, R³ and R⁴ are as defined in claim
 1. 11. A compoundof the Formula (21):

where A, B, C, D, R, R³, R⁴, R⁶ and R⁷ are as defined in claim
 1. 12. Acompound of the Formula (22):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined in claim
 1. 13.A compound of the formula:

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined in claim
 1. 14.A compound of the formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim
 1. 15. Acompound of the formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim
 1. 16. Acompound of Formula:

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim
 1. 17. Aprocess of claim 1 for the preparation of a compound of the Structure(k)

comprising the steps of (1) treating a compound of the formula

where R is as defined in claim 1, in an activation reaction to form acompound of the formula

where R and R⁷ is as defined in claim 1; (2) treating the product ofstep (1) with an acid chloride to form a compound of the formula;

where R and R⁷ is as defined in claim 1; (3) reacting the product ofstep (2) in an acylation reaction with a compound of the formula

where R⁸ is MgBr and R⁶ is benzyl or R⁸ is H and R⁶ OMe, to form acompound of the formula

where R and R⁷ are as defined in claim 1; (4) reacting the product ofstep (3) with the compound

in the presence of a palladium catalyst to form a compound of theformula

where R is as defined in claim 1 and X_(C) is as indicated above; (5)treating the product of step (4) with3,4-(methylenedioxy)phenylmagnesium bromide and a copper complex to forma compound of the formula

where R is as defined in claim 1; (6) treating the product of step (5)with sodium methoxide in methanol to form a compound of the formula

where R is as defined in claim 1; (7) treating the product of step (6)under acidic conditions to form a compound of the formula

where R is as defined in claim 1; (8) hydrogenating the product of step(7) over palladium on carbon to form the compound

where R is as defined in claim 1; (9) treating the product of step (8)with methyl bromoacetate, potassium carbonate in acetone/methanol,followed by saponification with lithium hydroxide monohydrate and acidicworkup to form the compound

(10) treating the product of step (9) with sodium hydroxide to form thefinal product, the compound


18. A process of claim 2 for the preparation of a compound of theStructure (s)

comprising the steps of (1) reacting the a compound of the formula

where R and R⁷ are as described in claim 17, with the compound

to form the compound

(2) reacting the product of step (1) with the compound

in the presence of a palladium catalyst to form a compound of theformula

where R is as described in claim 1; (3) treating the product of step (2)with 3,4-(methylenedioxy)phenylmagnesium bromide and a copper complex toform a compound of the formula

where R is as described in claim 1; (4) treating the product of step (3)with sodium methoxide in methanol to form a compound of the formula

where R is as described in claim 1; (5) treating the product of step (4)under acidic conditions to form a compound of the formula

where R is as described in claim 1; (6) hydrogenating the product ofstep (5) over palladium to form a compound of the formula

where R is as described in claim 1; (7) treating the product of step (6)with lithium hydroxide monohydrate, followed by acidic workup to formthe compound

(8) treating the product of step (7) with ethylenediamine to form thefinal product, the compound


19. A compound of claim 3 having formula

where R is as described in claim 1 and R⁷ is Br, I, —OSO₂CF₃or —OSO₂F.20. A compound of claim 4 having the formula

where R is as described in claim 1 and R⁷ is Br, I, —OSO₂CF₃or —OSO₂F.21. A compound of claim 5 having formula

where R is as described in claim 1 and R⁷ is Br, I, —OSO₂CF₃or —OSO₂F.22. A compound of claim 6 having the formula

where R is as described in claim 1 and X_(C) is as described in claim17.
 23. A compound of claim 7 having the structure

predominantly as the single diastereomer depicted.
 24. A compound ofclaim 8 having the structure

predominantly as the single enantiomer depicted.
 25. A compound of claim9 having the structure

predominantly as the single enantiomer depicted.
 26. A compound of claim11 having the formula

where R is as described in claim 1 and R⁷ is Br, I, —OSO₂CF₃or —OSO₂F.27. A compound of claim 12 having the formula

where R is as described in claim 1 and X_(C) is as described in claim17.
 28. A compound of claim 13 having the structure

predominantly as the single enantiomer depicted.
 29. A compound of claim14 having the structure

predominantly as the single enantiomer depicted.
 30. A compound of claim15 having the structure

predominantly as the single enantiomer depicted.
 31. A compound of claim16 having the structure

predominantly as the single enantiomer depicted.
 32. A process of claim1 for the preparation of compounds of Formula (19):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R¹ is

where R³ and R⁴ are independently H, OH, C₁₋₈alkoxy, F, CF₃ or C₁₋₆alkyland R⁵ is —OCH₂CO₂H; R² is

where R³ and R⁴ are as indicated above and Z is H, OH, or C₁₋₅alkoxy; ora pharmaceutically acceptable salt thereof, which comprises the stepsof: (1) treating a compound of Formula (10):

where A, B, C and D are as described above; and R is H, OH, C₁₋₅alkyl ofa protected oxy group, in an activation reaction to form a compound ofthe formula:

where A, B, C, D and R are as described above and R⁷ is Br, I,—OSO₂CF₃or —OSO₂F; (2) reacting the product of step (1) with an acidchloride to form a compound of the formula

where A, B, C, D, R and R⁷ are as defined above, and a compound ofFormula (t):

where R³ and R⁴ are as described above, R⁶ is OH or protected OH and R⁸is MgBr or H, to form a compound of Formula (12):

where A, B, C, D, R, R³, R⁴ and R⁶ as defined above and R⁷ is Br, I,—OSO₂CF₃ or —OSO₂F; (3) reacting the product of step (2) with thecompound

in the presence of a palladium catalyst to form a compound of theformula:

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (4)treating the product of step (3) with a compound of the formula:

where R³ and R⁴ are as defined above, with copper complex to form acompound of the Formula (14):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (5)treating the product of step (4) with sodium methoxide in methanol toform a compound of the Formula (15):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (6) treatingthe product of step (5) under acidic conditions to form a compound ofthe Formula (16):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (7)hydrogenating the product of step (6) over palladium to form a compoundof Formula (20):

where A, B, C, D, R, R³ and R⁴ are as defined above; (8) treating theproduct of step (7) with methyl bromoacetate, potassium carbonate inacetone/methanol, followed by saponification with lithium hydroxidemonohydrate and acidic workup to form a compound of the Formula:

where A, B, C, D, R, R³ and R⁴ are as defined above; (9) treating theproduct of step (8) with sodium hydroxide to form the final product, thecompound

where A, B, C, D, R, R³ and R⁴ are as defined above, predominantly asthe single enantiomer depicted.
 33. A process of claim 2 for thepreparation of compounds of Formula (19):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R¹ is

where R³ and R⁴ are independently H, OH, C₁₋₈alkoxy, F, CF₃ or C₁₋₆alkyland R⁵ is —OCH₂CH₂OH; R² is

where R³ and R⁴ are as indicated above and Z is H, OH, or C₁₋₅alkoxy; ora pharmaceutically acceptable salt thereof, which comprises the stepsof: (1) reacting the compound (11):

where A, B, C and D are as described above, R is H, OH, C₁₋₅alkyl or aprotected oxy group and R⁷ is Br, I, —OSO₂CF₃ or —OSO₂F; with an acidchloride to form a compound of the formula

where A, B, C, D, R and R⁷ are as defined above; and a compound of theformula:

where R³ and R⁴ are as described above, R⁶ is OH or protected OH and R⁸is MgBr, to form a compound of Formula (21)

where A, B, C, D, R, R³, R⁴ and R⁶ are as described above and R⁷ is Br,I, —OSO₂CF₃ or —OSO₂F; (2) reacting the product of step (1) with thecompound wherein X_(c) is

in the presence of a catalyst to form a compound of formula (22):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (3)treating the product of step (2) with a compound of the formula:

where R³ and R⁴ are as defined above, with copper complex to form acompound of the Formula (23):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined above; (4)treating the product of step (3) with sodium methoxide in methanol toform a compound of the Formula (24):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (5) treatingthe product of step (4) under acidic conditions to form a compound ofthe Formula (25):

where A, B, C, D, R, R³, R⁴ and R⁶ e as defined above; (6) hydrogenatingthe product of step (5) over palladium to form a compound of Formula(26):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined above; (7) treatingthe product of step (6) with lithium hydroxide monohydrate to effectsaponification and epimerization followed by an acidic workup to form acompound of the Formula:

where A, B, C, D, R, R³ and R⁴ are as defined above; (8) treating theproduct of step (7) with ethylene diamine to form the final product, thecompound

where A, B, C, D, R, R³ and R⁴ are as defined above, predominantly asthe single enantiomer depicted.
 34. A compound of claim 7 having theFormula (14):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined in claim 32,predominantly as the single enantiomer depicted.
 35. A compound of claim8 having the Formula (15):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim 32,predominantly as the single enantiomer depicted.
 36. A compound of claim9 the Formula (16):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim 32,predominantly as the single enantiomer depicted.
 37. A compound havingthe Formula:

where A, B, C, D, R, R³ and R⁴ are as defined in claim 32, predominantlyas the single enantiomer depicted.
 38. A compound of claim 13 having theFormula (23):

where A, B, C, D, R, R³, R⁴, R⁶ and X_(C) are as defined in claim 32,predominantly as the single enantiomer depicted.
 39. A compound of claim14 having the Formula (24):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim 32,predominantly as the single enantiomer depicted.
 40. A compound of claim15 having the Formula (25):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim 32,predominantly as the single enantiomer depicted.
 41. A compound of claim16 having Formula (26):

where A, B, C, D, R, R³, R⁴ and R⁶ are as defined in claim 32,predominantly as the single enantiomer depicted.
 42. A compound of theFormula:

where A, B, C, D, R, R³ and R⁴ are as defined in claim
 1. 43. A compoundthe structure

predominantly as the single enantiomer depicted.
 44. A process toprepare a compound of the structure

which comprises reacting a compound of the structure

with 3-Chloropropionyl chloride and a base.
 45. A process to prepare acompound of the formula

where A, B, C, D, R, R³ and R⁴ are as defined in claim 33, predominantlyas the single enantiomer depicted, which comprises reacting a compoundof the formula

A, B, C, D, R, R³ and R⁴ are as defined in claim 33, with ethylenecarbonate and a base, preferably potassium carbonate, at 90-115° C.,followed by treatment with lithium hydroxide monohydrate, to form thefree acid, followed by the addition of ethylene diamine.
 46. A compoundprepared according to claim 1.